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The Immune System and Its Ecology*
Alfred I. Tauber†‡
In biology, the ‘ecological orientation’ rests on a commitment to examining systems,
and the conceptual challenge of defining that system now employs techniques and
concepts adapted from diverse disciplines (i.e., systems philosophy, cybernetics, information theory, computer science) that are applied to biological simulations and model
building. Immunology has joined these efforts, and the question posed here is whether
the discipline will remain committed to its theoretical concerns framed by the notions
of protecting an insular self, an entity demarcated from its environment, or will shift
its focus of interest to a wider context. An ecological perspective emphasizes the interchange between the organism and its environment, the processing of information,
and the regulation arising from responses to this larger context. Moving from the first
attempts at modeling the immune system as a closed network, immunologists have
joined the general interest in systems analysis, and that move might portend a significant
shift to an open, more holistic consideration of immune regulation.
1. Introduction. How might immunology be regarded from an ecological
perspective? Indeed, why consider such a framework? At one level, this
project would appear to be an exercise already well traversed. After all,
the immune system is generally regarded as responsible for host defense
against invading pathogens. Immunology thus presents a primal example
of the interactions of species juxtaposed with each other and depicts how
either struggle or cooperation is enacted. From this perspective, how animals respond to insult and what comprises the mechanisms of defense
or silence seem fundamentally ecological in character. Yet the historical
development of the discipline reflects a deep-seated conceptual orientation
*Received December 2006; revised August 2007.
†To contact the author, please write to: Center for Philosophy and History of Science,
Boston University, 745 Commonwealth Ave., Boston, MA 02215; e-mail: [email protected].
‡I am indebted to Andrea Grignolio for assistance in researching the history of immune
models and information theory in immunology, a subject he is preparing for publication. I thank Richard Gunderman of Indiana University for alerting me to the term
‘ecotone’ and its meanings, as well as critical comments offered by Eshel ben Jacob
and Zvi Grossman. Portions of this paper have been modified from a previous publication (Tauber 2005).
Philosophy of Science 75 (April 2008) pp. 224–245. 0031-8248/2008/7502-0006$10.00
Copyright 2008 by the Philosophy of Science Association. All rights reserved.
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to an individual-based biology developed at the expense of a more comprehensive interactive ecology. The gains and losses of that approach are
becoming evident as immunology is belatedly directing itself towards a
systems-based understanding of immune regulation, which regards immune function as part of, and thereby regulated by, its broader context.
This shift has been slow in arriving, for the organizing model of immune
function for the last half century has been cast as the discrimination of
a ‘self’ from the ‘other’ (Tauber 1994; 1999; Podolsky and Tauber 1997).
Plainly, immunity is the mechanism by which a self, conceived as having
borders, defends itself. Indeed, immunology is often described as the science of discrimination between self and non-self, and it has fulfilled that
agenda by following a reductive exercise: defining the components of
immunity and their regulation as a self-contained system (Moulin 1991).
Accordingly, the self as a distinct, circumscribed entity could not have
been more divorced from its environment in this formulation.
This conceptual structure is hardly surprising. Since immunology was
born during the decipherment of infectious diseases at the end of the
nineteenth century, immunologists have generally adopted an insular perspective, where an entity is defended. Indeed, when elucidating reactions
against pathogens dominated immunology, a military metaphor of an
‘army’ of immune factors fighting to ‘protect’ the organism became standard currency. Not until the 1930s was the immune system considered as
part of a complex ecology, and then, only tangentially. Macfarlane Burnet,
a virologist by training, adopted “ecology” as part of a grand view of
biology in which he hoped to situate immunology beyond the narrow
confines of immunochemistry (Tauber 1994, 94–98; Crist and Tauber
2000). Inspired by the Science of Life, co-authored by H. G. Wells and
Julian Huxley, Burnet began to fashion a comprehensive view of biology
that would include ecology, developmental biology (with genetics), and
immunology (Wells, Huxley, and Wells 1929). With an emphasis on ecological succession and the plant community as a complex organism undergoing a life-cycle and evolutionary history, he appreciated, analogous
to the individual organism, parallels with the psychological self. Specifically, he regarded the triad—climax community (ecology), human body
(organism), and self (psychology)—as analogous constructions and thereby affirmed a deep organic connection at three different levels of organization: ecological, cellular, and individual organism, each of which were
structurally analogous and interconnected in a chain of being.
A profound irony then developed: In 1949, Burnet built upon the vague
notion of selfhood he developed from his reading of Science of Life (Burnet
and Fenner 1949) and formally introduced the notion of the immune self.
According to his theory, the immune system discerned host elements to
which it did not react, and those it failed to recognize as ‘self ’ stimulated
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an immune reaction. (The self was thus conceived as a ‘negative’ image,
i.e., that which elicited no response). The Burnetian self, introduced as a
metaphor of human personal identity, was consequently construed as
requiring defense, and the immune system assumed its original task of
protecting the host (the self) against pathogens.
So what began with a vague, metaphorical intuition about how immunity might function as a participant within a larger context, specifically
an ecological one, quickly was submerged by the dominant concern of
defining the immune self in molecular terms. Indeed, the immune self
became a powerful epistemological focus of defining biological individuality.
The first serious challenge to this theoretical formulation was offered
by Niels Jerne in 1974 with his proposed “idiotypic” immune system (Jerne
1974, 1985). Basically, Jerne postulated that the immune system consists
of antibodies recognizing other antibodies and lymphocytes recognizing
other lymphocytes through unique (idiotypic) domains. These distinguishing structures purportedly provide specific docking sites for the various
elements, which through these interconnections, self-organize into a vastly
complex interlocking system of joined antibodies and lymphocytes. The
‘network’ then rested in a stable state in its ongoing self-recognizing activity, but when a disturbance causes the lattice-like structure to readjust
its normal valenced connections, an immune reaction ensues.
The notion of idiotypes remains an eccentric contribution, and its final
status is still unresolved, but the main theoretical thrust of Jerne’s highly
integrated and self-sensing system posed a radical alternative to the selfnon-self Burnetian formulation: In Jerne’s theory, self and non-self dissolved as useful parameters of immune organization, because the idiotypic
network only saw itself. Self and other were no longer classes in this theory,
and thus immune reactivity became the parameter of interest, not selfhood
per se. Essentially, Jerne argued that the perturbation of intricately balanced feedback loops would trigger immune responsiveness. His theory
is characterized by the organizational principle of an inner driven, selforganizational model. If there is a self in Jerne’s theory, it is the entire
immune system as it ‘senses’ itself, but the distinction between self and
non-self has no standing. Jerne’s theory thus appears radically different
from the dominant theories of immune function built from Burnet’s dichotomy between self and non-self. Moving beyond the self, the issue
became ‘reactivity’—its initiation, its effector mechanisms, its controls.
The challenge posed by the network theory was twofold. Most generally,
it demanded a functional theory of immunity, one based on the cardinal
principle of an inward-directed self-seeking process; its critical weakness
was lacking a stable reference for defining its basis for reactivity. In the
older model, selfness served as the foundation of immune reactivity. Jerne
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substituted ‘perturbation’ to account for immune reactivity, leaving the
immune system to know only itself and thus both disqualifying and abdicating any responsibility for discriminating ‘self ’ and ‘other’.
Jerne’s theory appeared as growing perplexity about autoimmunity
drove some immunologists to ponder the utility of the self versus nonself discriminatory model as the basis for immune function. They have
long understood that the beneficial effects of immunity carries costs, since
the immune system is capable of apparently capricious assault on its host.
So called autoimmune reactions were described at the turn of the last
century, and later determined as cause of autoimmune disease, but because
the entire orientation of the science was to see immunity as a mediator
of host defense, these findings were viewed as a pathological aberrancy.
Arising from an unregulated killer system gone awry, autoimmunity, on
this view, could hardly be regarded as part of an expected continuum of
normal immune function (Tauber 1994). ‘Ideal’ immunity was the agent
of the self, and although there might be inconsistencies in behavior regarding that mandate, the basic structure of immunology demanded articulation of a model of identification and the protection of organismal
identity. However, autoimmunity is now regarded as a normal physiological function of the immune system, not so much in the Jernian sense,
but rather because immunocytes and their products survey and contribute
to normal body economy. From the clearing away of senescent, damaged
or dead cells to surveillance for malignancies, the immune system has a
robust immune profile of activity directed at host elements, normal and
abnormal. This understanding of immunity has served as a springboard
of criticism directed at the polarization between self and non-self (e.g.,
Coutinho and Kazatchkine 1994; Podolsky and Tauber 1997, 326ff.).
The major difficulty, however, is to define “the immune self,” which
has been notoriously difficult to do. There are at least half a dozen different conceptions (Matzinger 1994) that might be situated by where one
places the model on a continuum between a severe genetic reductionism
and a complex construct employing different principles of organization.
With so much dispute surrounding the definition of self, a growing counter
position suggests that the ‘self’ might be better regarded as only a metaphor for a ‘figure’ outlined by the immune system’s silence, that is, its
non-reactivity. That figure is inconstant and modified upon certain conditions. (For instance, pregnancy, where a fetus, clearly different genetically from its maternal host, enjoys immunological indifference.) A second
aspect of this imbroglio concerns immune reactivity where certain foreign
elements are ignored, for example, cooperative relationships, such as the
inactivity against symbionts that coexist in all organisms. (In humans,
the best studied case is the vitamin K producing bacteria of the intestine
(Ivanov, Diehl, and Littman 2006) that provide the cofactor required for
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components of the blood coagulation and energy metabolism). Because
immunology developed in the context of defensive functions, this cooperative biology and its complex teleology have remained obscured by the
dominant concerns generated by the threat of pathogens. Indeed, the
biomedical model has so dominated immunology that comparative immunology represents a small portion of the literature, and the specific
ways in which the immune system tolerates, or even fosters cooperative
relationships is smaller yet.
More to the point, the theory built upon ‘the self’ now appears to have
many ad hoc caveats and paradoxes. Perhaps the evolution of the original
metaphor to theory has begun to yield to another metaphorical construction (Tauber 1994). Here, we are putting aside this much discussed older
debate about the character of the dichotomy between self and non-self
that has framed immunology’s theoretical structure for the past half century to consider instead a complementary way of addressing these same
basic issues by focusing instead on an ecological orientation. That perspective already assumes a subordination of the individual to a collective
picture of biological function, and in place of differentiation, integration
and coordination serve as organizing principles. To this matter we now
turn.
2. Immunology and Ecology: Historical Considerations. An ecological perspective now seems to be asserting its own claims more effectively, largely
under the guise of systems biology. This development seems overdue.
Beyond the tacit connections between immunology proper and its kindred
disciplines of pathology, infectious diseases (human and veterinary medicine), and public health, the immune system as regulated by a larger
context demands an accounting. That context still remains undefined, but
the challenge of understanding autoimmunity and tolerance suggest that
immune regulation arises from complex dynamics, possibly from outside
the immune system itself as traditionally conceived. To broaden immunology’s conceptual framework, immunologists have joined the general
shift towards systems analysis that began to move the discipline from an
almost exclusive reductive strategy to a more holistic one. That history
is now briefly reviewed.
Immunology and ecology as modern disciplines were born almost simultaneously. Elie Metchnikoff formulated immunology’s first active theory of immunity within a Darwinian construct (Tauber and Chernyak
1991; Gourko et al. 2000; Tauber 2003). He was the first to accurately
regard phagocytic cells as engaged in a competitive struggle with invading
microbes, and in that formulation, we might say he adopted the ‘red in
tooth and claw’ attitude of the era. These initial immunological observations began at about the same time one of his competitors, Ernst
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Haeckel coined the term ‘ecology’. Haeckel, like Metchnikoff, was caught
up in the Darwinian fever of the 1860s, and Haeckel thought a term was
needed to refer to the study of the multifaceted struggle for existence,
which Darwin’s theory so clearly articulated. In 1866, Haeckel casually
mentioned ecology as the study of “the interrelationships of living beings
among themselves” and in 1870 elaborated this definition:
By ecology we mean the body of knowledge concerning the economy
of nature—the investigation of the total relations of the animal both
to its inorganic and organic environment; including, above all, its
friendly and inimical relations with those animals and plants with
which it comes directly or indirectly into contact—in a word, ecology
is the study of all those complex interrelations referred to by Darwin
as the conditions of the struggle for existence (cited by McIntosh
1985, 7–8).
Haeckel and many nineteenth century biologists considered ecology simply a branch of physiology. Indeed, two founders of the discipline, the
American botanists F. E. Clements and H. C. Cowles, described it as
identical to physiology (McIntosh 1985, 3), and by the 1890s, they and
others had initiated physiological studies of the relationships between
organisms and their environment. They were guided by the theoretical
supposition that nature was self-regulating and that balance, despite environmental changes of various kinds, remained operative in stable communities. Yet evolution ceaselessly exhibited how new challenges and opportunities required adaptation and so specific studies to comprehend
those dynamics were finally recognized as crucial for understanding Darwinism. Especially in the United States, a dynamic, experimental approach
to the study of adaptation, community succession, and population interactions made the early ecologist an “outdoor physiologist” (Kingsland
1991, 2). Despite the ‘physiological’ approach, ecology remained a distinct
discipline quite divorced from those life sciences focused on the organism.
Immunology clearly aligned itself with the biology of individuals, and
indeed, one might easily argue it became the science of individuality at
the expense of community.
Metchnikoff and Haeckel competed with each other in a number of
research areas, including the definition of embryonic germ layers and
hypothetical models of the first multicellular organism (Tauber and Chernyak 1991; Gourko et al. 2000). From those research interests, Metchnikoff went on to characterize the dynamics of the struggle between phagocytic cells and pathogens, while Haeckel remained within developmental
biology with notorious excursions into eugenics, race theory, and philosophy. Their respective stories are not directly germane to our present
concerns, other than to note that neither seemed to appreciate how eco-
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logical relationships might be formally characterized. They, like Darwin,
understood ‘struggle for survival’ in broad descriptive metaphors, and
being so focused on the response of the host organism against pathogens,
these zoologists never peered seriously beyond the individual to situate
the animal within its greater environment—that development awaited the
twentieth century.
Three definitions of ecology structure the modern literature: (1) a
Haeckelian form—the study of the relationships between organisms and
environment; (2) the distribution and abundance of organism—a population-centered ecology; and (3) the study of ecosystems—the most encompassing, moving from an emphasis on organisms to a comprehensive
study of the structure and function of nature. One might assume that a
holistic attitude dominated ecological thinking from the inception of the
discipline, but the concept of the ecosystem emerged slowly (Golley 1993).
Indeed, since the 1950s, contemporary ecology theory has developed
around a core of issues, each of which may be seen as adopting, at least
implicitly, a systems orientation: (1) community populations; (2) niche
theory; (3) population dynamics of single species; (4) multi-species interactions; (5) population structure, and (6) the implications of individual
behavior on population phenomena (Real and Levin 1991, 177).
The first version of general systems theory was presented in the context
of multi-species interactions. These were the mathematical models (produced between 1910 and 1920) of Sir Ronald Ross and W. R. Thompson,
which were based (ironically!) on host-parasite epidemiology (Kingsland
1985). This work was developed in the 1920s by A. J. Lotka and Vito
Valterra, who demonstrated oscillatory predator-prey dynamics (Real and
Levin 1991, 187–188). Yet ecosystem, as such, awaited another context.
Although A. G. Tansley, a British plant ecologist, introduced the term
‘ecosystem’ in the context of a super-organism plant community, Raymond Lindeman ([1942] 1991) outlined what became ecosystem ecology
by (1) emphasizing quantitative relations in determining community patterns through succession; (2) identifying the dynamic process of energy
flow, and (3) adopting a theoretical orientation in ecology (McIntosh 1985,
193ff.). Eugene Odum’s influential textbook (1953) formally brought this
systems-based thinking to modern ecology. Initially organized around the
measurement of energy flow through the system (the first example was
the study of a lake), this ‘new ecology’ expanded its horizons quickly to
deal with “the structure and function of levels of organization beyond
that of the individual and the species” (Odum quoted by McIntosh 1985,
200), which Odum expanded into a new biology: Ecology is “not just a
subdivision of biology, but a new discipline that integrates biological,
physical, and social science aspects of man-in-nature interdependence”
(quoted by McIntosh 1985, 202). The ethos of the discipline was now
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guided by a holistic ideal, which would integrate the component parts
and consider the ecosystem as a hierarchical unit (O’Neill et al. 1986).
The influence of this orientation eventually permeated the organism-based
sciences, including immunology.
3. A Conceptual Shift? An obvious way of approaching the immune system ecologically is to consider the overall adaptation of the individual,
as well as the species-as-a-whole, within its environment. Characterized
by population dynamics, the competitive context is traditionally assessed
by predator relations, cooperative behaviors, food sources, environmental
effects, and so on. Immunity is another important measurement of these
relationships. How microbe and host relationships maintain stability, and
perhaps just as important, how equilibriums are disrupted, provides a key
parameter by which individuals and species competition are defined in
the medical, economic, and agricultural disciplines. If one seeks a teleological explanation of immunity, survival and fitness certainly present a
rich basis for sorting out immune behavior.
Because the immune system resides at the interface between the organism and its environment, it is fairly regarded as a first line of defense, or
more broadly an information processor for the host organism. While
immune cells distribute themselves throughout the body, they are particularly conspicuous at the interfaces between host tissues and the environment: within the skin and underlying muscosal surfaces (e.g., the respiratory tract and gastrointestine). These are the sites where the body
first encounters chemicals and micro-organisms, and thereby senses toxins
and destroys pathogens. Such interfaces are obviously open and dynamic,
and they possess a complexity distinct to themselves.
Ecologists refer to such transition sites of adjacent ecological communities, for example, forest and grassland habitats, as an ecotone. ‘Ecotone’ is derived from eco-, ‘house’ or ‘household’, and the root tonos, the
source of the word ‘tone,’ which means ‘act of stretching or tension’ (i.e.,
‘tone’ is produced from a stringed instrument). The ecotone then is both
the ‘home’ of certain species, but also one in which new tensions, or
opportunities, arise. The notion of an ecotone captures the biological
richness and diversity of comingled species interacting in the same space,
and more to our concerns, the ecotone explicitly frames the reference of
study to include both the microbe and the host animal. Because such
border areas contain species from each habitat, unique forms of competition may occur, giving rise to unique dynamic relationships. From
one perspective, new competition means facing new threats, but from
another vantage, new opportunities arise in such an environment. From
a quite different point of view, ecotones may be seen as engines of biological innovation. Diversity and dynamism are greatest at the margins
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between habitats, and it is at such interfaces that whole new biological
forms probably originated. Far from being places of pure strife, some
ecotones are characterized as much by cooperation and synergism as by
cutthroat competition. How might immunologists formally utilize this
context in which to conduct studies relevant to ‘ecological physiology’?
4. Introducing Systems Biology to Immunology. To adequately address the
larger dynamics that must account for the coexistence of interacting species, a systems approach is required that is capable of accounting for the
behaviors of the immune system—both of individuals and that of the
population’s collective immunity. Such a study presents the language of
a dialogue between individual organisms and their environments in response to the challenges received from diverse encounters. In short, the
immune system functions at the interface of host organism and its environment both defensively and cooperatively. Immunity accomplishes
that task in a two step process: First, as a cognitive system, one responsible
for perceiving the environment, and second, as enacting appropriate responses to that environment. By first framing immunity as perception,
regulation becomes a process arising from both internal equilibrium mechanics and stimulation from external sources. A systems approach accounts for both, and here I will explore the conceptual resonances between
three different organizing orientations: ecological, cognitive, and systems
biology.
Cognitive functions are fundamentally open, and thus immune theory
should describe how immune system design permits, and then responds
to, open information flow. Given these general concerns, immunology
already has the conceptual infrastructure to assume a fuller ecological
orientation—placing immune reactivity (regulation) within an environment of inputs. So beyond understanding how a particular antigen might
be regarded as harmful to a particular individual or species (and thus
subject to immune destruction), the wider reference of ‘ecological immunology’ attempts to determine the costs of defensive mechanisms to
the community-at-large1 (Sheldon and Verhulst 1996; Norris and Evans
2000). That understanding requires a systems biology approach firmly
1. Note, ‘ecological immunology’ is not the same concept as ‘immuno-ecology’, which
Charles Orosz defines as “the study of the immunological principles that permit effective
immunologic function within the context of the immensely complex immunologic network” (2001, 125). Orosz is seeking to understand the immune system as an ecology,
but he makes no effort to ‘open’ that system in the way I describe here, i.e., to place
the animal within its larger environment and turn immunology into an ecological
science. Elling Ulvestad’s Defending Life (2007; reviewed by Tauber [2008]) qualifies
as the most comprehensive treatment to date of the ‘ecological consciousness’ described
here.
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planted in information theory, which then reaches beyond the organism
to its placement within it environment: Information theory represents the
window by which the organism must be understood as living in an environment it must know in order to survive.
The first step along the path that will decipher this cognitive structure
requires a re-formulation of an atomistic conception of immune selfhood,
namely that an entity, ‘a self ’, exists to be defended against intruders
(Janeway 1989). However, just as important as the offensive weaponry
might be, the ability to remain ‘silent’ (tolerant), to live in a world of
others, must also mark immune function. Immune tolerance, the absence
of reactivity, also distinguishes the immune system as a cognitive apparatus. Thus, neither indolent innocence nor persistent aggression captures
the activity of the immune system, which must function within a changing
environment of friend and foe. Defining the off or on status of immune
reactivity is not simply a question of identifying the ‘other’, but involves
multiple stages of sensing, adjusting, and configuring immune reactions—
positive and negative—in settings that vary in time and space.
Immunity ranges from a ‘pre-immune’ state, whereby immune cells
sense the presence of bacteria well before their formal encounter, to full
blown activation (Germain 2001). ‘Priming’ events signal the sensitive
connections of an ecological state—bacteria and immune system—in
which a web of molecular links communicate the presence of ‘the other’.
This ecological orientation brings issues of communication and information theory directly onto notions of immune regulation, where different
tiers of bidirectional cognition between pathogens and immune cells set
the balance of responses and adaptation. Indeed, ‘immune cognition’—
replete with metaphorical ‘memory’, ‘perception’, and ‘recognition’—has
already provided a new scientific lexicon for a variety of converging conceptual orientations (Tauber 1997).
Immune cognition has been appropriated by immunologists of widely
differing theoretical orientations. On the one hand, it has been used to
describe the MHC-lymphocyte encounter as a perception event to be
understood by the reductive strategies employed by those descendents of
the immunochemists, who sought definition of the immune reaction in
terms of the most basic molecular mechanisms. On the other hand are
those theorists who seek to model the immune system in terms of its
global properties, understanding cognition as analogous to the emergent
properties of the mind. These conflicting uses of cognition have long
antecedent historical roots, which reflect differing cognitive models
(Tauber 1997).
In the 1990s, various theoretical speculations about immune ‘dialogue’
with the body emerged from this cognitive orientation. Surveillance and
autoimmunity framed Irun Cohen’s model, in which the immune system
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continuously exchanges molecular signals with its interlocutor, the body
(Cohen 1992, 1994). Zvi Grossman placed the reactive lymphocyte in a
medium of varying activation states that were set by the larger inflammatory context (Grossman and Heberman 1986; Grossman 1989; Grossman and Paul 1992), an idea further developed by Polly Matzinger, whose
contextualist orientation explicitly extended immunity to include an array
of physiological functions, each of them now regarded as fully integrated
with the organism-as-a-whole (Matzinger 1994; Anderson and Matzinger
2000a, 2000b). She formulated the immune system as interlocked with
every compartment of the body, and thereby regulated in response to
‘danger’ signals that might arise from any tissue subject to injury or insult.
The ‘meaning’ of immunogenicity, that is, reactivity, in this format is
situated within a larger functional framework, for example the sense of
‘danger’ ensuing from inflammation (Matzinger 1994).
These theorists agreed that antigenicity, then, is only a question of
degree: healthy host constituents are assessed and ignored; damaged or
senescent host elements evoke responses ranging from vary degrees of
tolerance to active destruction, and that regarded as ‘foreign’ suffers full
blown assault. These conceptions of the immune system thus highlight
immune activity engaged in ongoing sensing of the organism itself as
immunocytes constantly survey their jurisdiction (Schwartz and Cohen
2000). This move from a simple on or off switch heralds a decisive shift
in immunology’s theoretical foundations, one more attuned to the diversity of immune functions, and the various modalities of activation, which
contribute to evolutionary fitness (Cohen 1992, 1994; Grossman and Paul
1992; Stewart 1994b; Tauber 2005). Note, however, these models were
contextually driven, but still not fully ecological, inasmuch as the host
organism formed the boundaries of regulation.
From an ecological perspective, there can be no circumscribed, self
defined entity that is designated the self (Tauber 2000; alternate views are
given in Langman 2000). Rather, the organism adjusts its own identity
as it responds along a continuum of behaviors to adapt to the challenges
it faces, and, indeed, ‘identity’ is determined by particular context. Responses are consequently based not on intrinsic foreignness, but rather
on how the immune system sees an ‘alien’ or ‘domestic’ antigen in the
larger context of the body’s economy (Grossman and Paul 2000; Horn
et al. 2001). So, while host defense is a critical function, it is hardly the
only one of interest. Indeed, the immune system might be regarded as
primarily fulfilling an altogether different autoimmune role if its resting
physiology is measured and its phylogeny carefully examined. On this
basis, John Stewart has provocatively suggested that the immune system
became defensive only after its primordial neuroendocrine communicative
capabilities were usurped for ‘immunity’ (Stewart 1992, 1994b). Accord-
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ingly, immunology becomes part of a more comprehensive psychoneuroimmunology, which defines immunity as a cognitive activity coordinated
with other cognitive systems (Ader et al. 2001). To model such complex
behavior, a systems approach seems appropriate. Movement toward this
goal is evident, but what is systems biology?
5. A New Approach? Systems biology applied to ecology, as already reviewed, is not new. And in immunology, early stirrings appeared in the
1950s under the mantle of cybernetics. Indeed, both ecologists and immunologists were intrigued with the promise of cybernetics for their respective disciplines, but the hopes were largely frustrated, inasmuch as
direct application of Shannon-Weaver formalisms failed (McIntosh 1985,
210–213; Tauber 1994, 161–165). But frustration ran deeper. The cybernetic movement was actually part of a larger systems approach, one which
drew from several sources. As a result, the discipline has had difficulty
melding itself into some unity, indeed, some would argue that systems
biology has never come to peace with its own definition. No wonder, inasmuch as it is a mosaic of six theoretical programs (Lilienfeld 1978):
1.
2.
3.
4.
5.
6.
Systems philosophy (von Bertalanffy 1968; Laszlo 1972; Patten
1975);
Cybernetics (Ashby 1956; Weiner 1961);
Information theory (Shannon and Weaver 1949);
Operations research;
Game theory (von Neumann and Morgenstern 1947);
Computer simulation of complex systems (e.g., Forrester 1961).
According to this schema, a philosophy underlies the technical enterprise, and cybernetics, coupled to information theory, serve together in
various guises in the modeling of complex systems. Which horse will lead
the chariot is still unclear. Different systems may require different sorting
of the various components, but more fundamentally, systems biology lacks
a specific definition and has no specified method, so perhaps proponents
follow an intuition, which skeptics regard as a promissory note (at best).
Accordingly, systems biology seeks to supplement an older reductionist
analysis of complex biological phenomena with an integrative strategy
that would combine the various elements into a coherent, dynamic whole
(Woese 2004).
Conceptually, modeling has been divided two distinct strategies. (1) A
holistic approach treats the system as a black box and considers only
inputs and outputs, in contrast to (2) a mereological (reductionist) approach, which builds the system from its component parts. Despite their
obvious oppositions, these conceptual roots are revealing and potentially
important. Integrative, holisitic, contextualist and organicist approaches
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each refract a reaction against analytic atomism and combine to suggest
a major reorientation in scientific thinking—from Cartesian reductionism
to something else. However, at this point, depending on its various applications, systems biology has several personifications, and most would
agree, based on projected experimental suggestions or predictive applications, systems biology has yet to ‘deliver the goods’.
Levins and Lewontin correctly observed that the computer models of
25 years ago were not holistic, but rather only expressions of large scale
reductionism (1985). That criticism still holds among many skeptics as
they await a major breakthrough (Mekios 2007). While the contemporary
agenda remains holistic in sentiment, the question remains whether system-wide principles may be discerned beyond the assembly of connected
discrete elements determined by relationships formed at their own level.
Proponents say all the right things: Their approach aims at a “systemlevel understanding of biological systems,” which includes the identification of a system’s structure, behavior, control, and design (Kitano 2001,
2–4). Presumably this includes establishing, for various biological systems—cellular (metabolic, genetic), physiological (e.g., immune, neuroendocrine), and ecological—their large-scale organization, regulation, information processing, and integration with other systems.
Immunology’s basic theory may well be in a transition period, but it
is simply too soon to decide. Without presenting some singular method
for immunologists seeking their own recipe to mix these various elements,
suffice it to note that as a cognitive system, immune reactivity requires
information theory, that is, the means by which the organism knows its
environment. (Here, I am referring to information theory as the window
by which to conceptualize the transition of latent information to some
active form, that is, information that is selected and then processed. Or
as John Nicolis quipped [1991, viii], “Information is an a posteriori measure of an a priori uncertainty, i.e., lack of predictability.”) By better
understanding how information is selected, regulatory mechanisms will
be both deepened and broadened. In short, models based on systems
analysis presumably will push immunology towards a larger ecological
conceptualization for understanding immune regulation.
6. Formalizing Immunology. The applications in ecology of differential
equation modeling and computer simulations began in earnest during the
1950s (Neel and Olson 1962), while immunology lagged behind by almost
25 years. Computer modeling, most closely related to Shannon information theory, was first used by Alan Perelson in the mid-1980s (Farmer
et al. 1986). This programmatic paper contained no data, only differential
equations that sought to formulate an immune system ‘learning machine’.
The modeled system was based on the self-contained network proposed
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237
by Jerne (1973, 1974). The development of this approach may be traced
to Jerne’s suggestion that the immune system was analogous to a translation-reading machine (Jerne 1960), and, indeed, Perelson’s paper employed ‘bits’ and 0–1 nomenclature. Noteworthy, Perelson, and virtually
all who followed him, were dependent on an immune system model that
was self-contained and self-regulated. They would design a system, but
it was a closed system, and in that very formulation, a wider systems
biology was beyond reach.
Shortly thereafter, Perelson (1988) edited two volumes of papers dedicated to immune modeling and with Tom Schneider’s “sequence logos”
approach (Schneider and Stephens 1990), the field began to attract some
interest and other approaches soon followed (e.g., Atlan and Cohen 1989;
Cohen and Atlan 1989; Vertosick and Kelly 1989; Stewart 1994a). Schneider graphically represented an aligned set of binding sites and proteins
measured in Shannon bits of information, which threw open the door to
artificial immune systems, bioinformatics algorithms and computational
biology. Led by advances in connectionism then popular in the neurosciences, these modelers pushed on despite recognizing that the limits of
the linear dynamics were insufficiently robust to deal with the complexity
of such systems.
The ‘systematic’ strategy requires high output, comprehensive data from
simultaneous measurements of multiple features. For example, to obtain
a complete understanding of gene regulatory networks, various simulations and analyses must be performed in order to assess binding constants;
rates of transcription and translation; kinetics of chemical reactions, degradation, diffusion; speed of active transport, and so on. Thus simultaneous study at several different levels of cellular organization are required.
Drawing strong analogies from engineering, admittedly a big assumption
(Kitano 2001, 18; Heinemann and Panke 2006), enthusiasts argue that
biological systems achieve robustness and stability through the same principles with which we build machines, namely using system controls (e.g.,
feedback), redundancy (e.g., gene duplication, alternative metabolic pathways), modular design (to minimize damage to local units), and structural
stability. From a systems perspective—perturbation of the dynamics dependent on diverse and multiple causes, coupled to complex controls—
result in altered network activities. Nonlinear, probabilistic, mathematics
are required to model such behavior, and so the resultant simple mechanical machine models will be replaced by different kinds of formalisms.
Moving from the theoretical to the practical, one strategy calls for the
establishment of a ‘systeome’, an assembly of system profiles for all genetic
variations and environmental stimuli responses of a cell. Unlike a cascade
map, a systeome would provide active and dynamic simulations of various
system statuses, as opposed to a static entity. Hiroaki Kitano has sug-
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gested, analogous to the Human Genome Project, a ‘Human Systeome
Project’, which endeavors to complete a detailed and comprehensive simulation model of the human cell at an estimated error margin of 20 percent
by the year 2030, which would include identifying the system profile for
all genetic variations, drug responses, and environmental stimuli (Kitano
2001, 25). From such analyses, the argument goes, elucidation of what
appears as emergent phenomena of complex systems will have a material
basis (Kitano 2001; Hood 2002; Alm and Arkin 2003; Mekios 2007).
Those seeking a New Biology might well herald systems biology as an
antidote to “molecular biology’s obsession with metaphysical reductionism” (Woese 2004, 179), and immunologists seeking the elucidation of
complex regulatory mechanisms have joined this new effort.
Indeed, much has changed since the early attempts at immune system
analysis, where a simple dichotomy between self and non-self framed
simple linear, mechanical model of on or off switches (i.e., ‘self ’ and ‘other’
reflect the binary decisions of such mechanisms). But in systems based
on nonlinear dynamics, where control mechanisms arise from many
sources and effects are realized by the summation of signals in a complex
calculus, how could such a dichotomous picture survive? If regulation
were understood in terms of the fine tuned accession of responses, as
opposed to the simplified on or off setting of discrimination between self
and non-self, more sophistication would be required. Such a reformulation
may develop as a result of the growing understanding of system analyses,
and, indeed, the advent of systems biology is beginning to impact on
immunology.
‘Immunocomputing’, or artificial immune systems, has drawn on recent
developments in computer science, information processing, pattern recognition, language representation and knowledge based reasoning (e.g.,
Tarakanov et al. 2003; Cohen 2007), and, in turn, immune based system
analysis is regarded by some as a fruitful source for applications to pattern
recognition, fault and anomaly detection, data analysis, scheduling, machine learning, autonomous navigation and control, search and optimization methods, artificial life, and security of information systems (de
Castro and Timmis 2002). The first textbook devoted to immunological
bioinformatics and the goal “to establish an in silico immune system”
(Lund et al. 2005, ix) has been followed by a surge of interest and speculation (e.g., Bersini and Carneiro 2006; Flower 2007; Flower and Timmis
2007). As one enthusiast opined, “after . . . 100 years of empirical research, immunology is hovering on the brink of reinventing itself as a
quantitative, genome-based science . . . whether or not the multitude of
practitioners of immunology wish to acknowledge it” (Flower 2007, 2).
The strategy offered is a stepwise approach, where models of discrete
immune phenomena (e.g., diseases, immune reactions, vaccines) or per-
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239
haps more modestly, function of various cell types, might be combined
into larger models. Thus quantitative modeling requires an analysis at
several levels—comparative genomics and proteomics, co-evolution with
pathogens, tissue-specific processes, population dynamics, cell turnover
kinetics, and regulation networks. This multidisciplinary approach includes bioinformatics, genomics, proteomics, cellular, molecular, and clinical immunology modeling, and ultimately, mathematical descriptions and
computer simulations.
Protein-protein and protein-peptide interactions are key to the recognition process and the overall functionality of the immune response, and
thus proteome-wide knowledge of such interactions is essential. Due to
novel high throughput techniques, interaction data are quickly developing
and the databases have already provided new initiatives for modeling and
systems analysis. Once protein-protein interaction networks are better
established, these may then be integrated with more sophisticated organizational models of cell-cell interactions and the cytokine network that
regulates them. The cellular field has developed in parallel with the protein
analysis, but as the system is studied at finer and finer levels of resolution,
decreased predictability in the behavior of any particular unit of function
(e.g., a gene, a cell) decreases (Germain 2001). Nevertheless, simulation
computer graphics have been used to produce and direct an animation
of T lymphocytes and other cells moving, interacting, multiplying, differentiating or dying in the course of development in the thymus (Efroni
et al. 2003). The simulation allows analysis of individual cells and their
component molecules as well as the ability to view thousands of cells
interacting in the formation of the thymus. Whether such computational
modeling reveals self-regulatory properties of the immune system (Cohen
and Harel 2007) remains to be tested experimentally.
7. Conclusion. Despite reasonable skepticism, the systems biology movement with its holistic aspirations has, at the very least, supplemented the
present fixation on reductionism. As many intuited during the past decade
that older approaches had reached some nebulous limit, a new enthusiasm
for a bona fide systems-based biology appeared. With this shift to a global
or holistic construct, concomitant with the technology to achieve these
ends, biology may be moving towards realizing concepts already evident
with Aristotle. Indeed, from De Anima to twentieth century physiology,
holism has held its position in biology, albeit subordinate to the prevailing
reductionist strategy. Now, with the multitudinous generation of data
emerging from genetics and cell biology, biologists must seek new means
of analyzing their findings, which requires the synthesis of vast amounts
of data. The field of bioinformatics was thus born, and with it systems
biology. If successful, the current emphasis on reductive analyses will be
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seen as closed and ironically incomplete. Some would argue that such a
shift has been overdue.
Modern biology has been committed to the physical and epistemological reductionism originally developed by Hermann Helmholtz and other
German physiologists in the mid-nineteenth century (Galaty 1974; Lenoir
1982). This philosophy has focused research efforts at defining the various
elements of complex organic processes, and then only as a secondary step,
attempting to bring those parts into coherent wholes. Through that strategy, twentieth century biochemistry, cell biology, molecular biology, and
immunology have each constructed increasingly complex structures to
depict life processes, but the ability to reassemble the elements back into
the wholes from which they were partitioned have been stymied, because
the simple mechanical models that have been employed for a century
(Loeb 1912) cannot account for the regulatory dynamics exhibited by
such complex phenomena.
In the case of immunology, the context of immune reactivity has demonstrated that simple on or off responses and feedback loops are insufficient for explaining immune function. The extracellular milieu of the
lymphocyte is a critical determinant, and that larger context must be
understood as encompassing ever-increasing domains (tissue, organism,
external environment). And even at the single cell level, the condition of
the local cell surface, the scene of interacting accessory molecules (e.g.,
cytokines), have long been known to mediate the immune reaction through
various modulations (e.g., Grossman and Paul 1992; Banchereau 1994).
The cytokines comprise hundreds of mediators and their receptors controlling dozens of functions. They exhibit the same general functional
properties of other bioactive peptides: in one setting, an agonist may
exhibit stimulatory properties, whereas in another, inhibition (Denny
2001). Indeed, clues from the cytokine system suggest designs for a distributed autonomous control network that must be dynamic, robust to
small perturbations, and yet responsive to large disturbances (Forrest and
Hofmeyr 2001).
Because the physiological role of any antigen or cytokine is determined
by a larger context than simply binding to its receptor, effects cannot be
predicted within a narrow domain of inquiry, because (1) signals of different integrated strengths evoke different responses; (2) the mode of response depends on timing of signal events; (3) activation thresholds may
be ‘tuned’ so that some lead to an enhanced state, while others become
inhibitory so that molecular agents may operate as an agonist or an
antagonist, depending on the adapted state of the cell (Podolsky and
Tauber 199, 352ff.). These characteristics must guide models that would
address how the discriminatory challenges facing the immune system require balancing immune protection, damage to the host, and physiological
THE IMMUNE SYSTEM
241
(normal) autoreactivity (Grossman and Paul 2000, 2001), within the larger
context of the organism’s place in its ecosystem, where cooperative relationships must also thrive. Coupling these various layers, lines of regulation dramatically multiply. In short, to explain immune reactivity, functions must be placed within larger teleological constructs, and how these
are drawn already assumes a limited domain of what must comprise an
integration of all levels of directed responses.
On this view of immune regulation, the various biochemical cycles of
intermediate metabolism drawn in the 1950s appear simple and refreshingly clear, where homeostasis became the sole parameter of assessment.
The successes of those depictions now appear as resulting from a smaller
scale of detail, the more simplified on or off character of the described
reactions (relatively few components integrated by single positive- and
negative-feedback connections), and most importantly from our point of
view, the singular teleology of homeostatic balance in which biochemical
functions were framed. With the advent of contemporary molecular studies, such an approach has become fraught with technical and conceptual
difficulties.
Whether we are now witnessing stirrings of an effective alternative
approach or only the excitement of a misconceived venture remains for
experimentalists to determine. I remain agnostic about the outcome, but
as a philosopher, I regard systems biology as an organizing idea supportive
to an alternative formulation of the immune system. So beyond systems
biology applied to immunology as a technical matter, a fully ecological
perspective (supported by systems biology more generally) would alter
the basic postulates of immune theory based on an insular self. Instead
of a theory grounded on self/non-self distinctions, models of the immune
system would be built on an ‘open’ architecture to fully represent the
dynamic and dialectical relationship characterizing an organism engaged
in its environment. Note, a systems approach may be applied to either
the self/non-self or ecological conception of immunity, and so conceptually,
the arguments for and against these competing views provide the arena
for the philosopher’s own discourse, one that has repercussions for philosophy of biology at large.
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